13-48303995-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4BP6BS2_Supporting

The NM_000321.3(RB1):c.83C>T(p.Pro28Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000446 in 1,345,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P28R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000045 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.83

Publications

5 publications found

Variant links:

Genes affected

RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

RB1 Gene-Disease associations (from GenCC):

hereditary retinoblastoma
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
retinoblastoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
melanoma
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

RB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29314122).

BP6

Variant 13-48303995-C-T is Benign according to our data. Variant chr13-48303995-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 568297.

BS2

High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.83C>T	p.Pro28Leu	missense_variant	Exon 1 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.83C>T	p.Pro28Leu	missense_variant	Exon 1 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.83C>T	p.Pro28Leu	missense_variant	Exon 1 of 17		NP_001394095.1
RB1	NM_001407167.1 link	c.83C>T	p.Pro28Leu	missense_variant	Exon 1 of 3		NP_001394096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.83C>T	p.Pro28Leu	missense_variant	Exon 1 of 27	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000446

AC:

AN:

1345604

Hom.:

Cov.:

AF XY:

0.00000603

AC XY:

AN XY:

663668

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27118

American (AMR)

AF:

0.00

AC:

AN:

30504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23684

East Asian (EAS)

AF:

0.00

AC:

AN:

31510

South Asian (SAS)

AF:

0.0000132

AC:

AN:

75498

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33500

Middle Eastern (MID)

AF:

0.000247

AC:

AN:

4042

European-Non Finnish (NFE)

AF:

0.00000376

AC:

AN:

1063786

Other (OTH)

AF:

0.00

AC:

AN:

55962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinoblastoma

Uncertain:1Benign:1

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Aug 03, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23516486) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P28L variant (also known as c.83C>T), located in coding exon 1 of the RB1 gene, results from a C to T substitution at nucleotide position 83. The proline at codon 28 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.35

T;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.57

T;T;T

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.69

N;.;.

PhyloP100

2.8

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.33

N;.;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.018

D;.;.

Sift4G

Uncertain

0.012

D;.;.

Polyphen

0.048

B;.;.

Vest4

0.31

MutPred

0.31

Gain of catalytic residue at P23 (P = 5e-04);Gain of catalytic residue at P23 (P = 5e-04);Gain of catalytic residue at P23 (P = 5e-04);

MVP

0.88

MPC

0.45

ClinPred

0.60

GERP RS

3.8

PromoterAI

0.14

Neutral

(source)

Varity_R

0.15

gMVP

0.17

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over